Overview

an administrative change such as a change of company name and/or address

a change to the characteristics of a product that can affect its quality, such as a change to its composition

a change to the safety, efficacy or pharmacovigilance of the product

Changes are classed as major (type II) or minor. Minor changes are either type 1A or 1B.

You can apply for:

a single change to one marketing authorisation (MA)

multiple changes to one or more products and/or MAs

Minor variations

These are divided into 2 types: IA and IB.

Type IA change

Type IA changes have little or no impact on the quality, safety or efficacy of the product, for example administrative modifications such as:

the manufacturer’s name

a minor change to a control method

deleting details of where the product is packaged

Type IA procedures are classed ‘do-and-tell’, where you should implement the change before you notify MHRA, ensuring that where relevant (non-immediate notification) you submit the application within 12 months. If the implementation period passes 12 months without a variation being made, a default Type 1B should be submitted. The MHRA will take up to 30 days to process your application.

Type IAIN change (immediate notification)

Type IAIN is a sub-type of type IA and also classed a ‘do-and-tell’ procedure where MHRA requires ‘immediate notification’, within 2 weeks of the change being implemented. A minor change would usually be type IAIN if it interferes with MHRA’s ability to continuously supervise the product.

All relevant conditions and documentation must be met for a Type IA/IAIN and confirmed in a copy of the classification guideline with either a tick or where not relevant, Not Applicable (N/A).

No ‘requests for further information’ (RFI’s) apply to Type IA procedures and there is no fee associated with a National Type IA/IAIN. A full fees list and further information about fees, can be found in the section fees for licence variation applications.

Type IB change

If the change is more significant than a IA change but is not a type II change or an extension, it is considered a type IB change. MHRA must approve type IB changes before they are made to the product.

Once MHRA has all the necessary documents, it takes up to 30 days to process your initial application. You could be given a further 30 days to respond to any requests for information letter, which for Type IB are referred to as Notification with Grounds letters (NWG).

These are seen as a conditional determination of a type IB variation, where the applicant has one opportunity to address any deficiencies or omissions.

There is a 30-day deadline to respond to a NWG otherwise the variation will be withdrawn or refused, this also applies if only a partial response has been received by the 30-day deadline.

Major variations (type II)

These changes are more complex and may have a significant impact on the quality, safety and/or efficacy of the product.

MHRA needs to approve major variations before they are made. One example of a major change is adding a new therapeutic indication to a product or updating the current indication (the medical needs the product is used for).

Once MHRA has all the documents, it will take 30, 90 or 120 days to assess your application depending on how urgent or complex the changes are, excluding time taken to answer questions.

Once MHRA has all the documents, it will take 22-days, (reduced timetable), 60-days (standard timetable) or 90-days (extended complex timetable) to assess your application depending on how urgent or complex the changes are, excluding time taken to answer questions.

With questions (RFIs), assessment timeframes become 30, 90 and 120 days respectively.

Response received-clock on completion of processing (excluding clock off time)

By day 30

By day 90

By day 120

A reduced Type II procedure (reduced from 60 days to 30) is for variations concerning safety issues and is agreed between the MHRA and the Marketing Authorisation Holder (MAH) and in general will be changes to the SmPC, requested following the assessment of a Periodic Safety Update Report (PSUR) or at the request of the MHRA Pharmacovigilance Unit.

Common invalidation errors and pre-submission checklist

Following analysis of submissions MHRA has developed a pre-submission checklist of submission errors. Applicants are strongly advised to use the pre-submission checklist below which will reduce the likelihood of the submitted application being invalidated or rejected.

The marketing authorisation holder (MAH) is responsible for ensuring that, where relevant, all relevant conditions and documentation are met and the submission of this information and dossiers are the most recent and up-to-date. Deficient or incorrect documentation can lead to invalidation and/or rejection of the variation.

Extensions

Although extensions are still considered a type of variation, their impact on a product is so significant that you will need to follow the application process to apply for a new MA. The form for this process has a section on extensions.

Extensions can be:

changes to the active substance(s), including the salt/ester, isomer or biological active substance

Revised labels, leaflets and/or packaging

If your variation (eg change of manufacturer) affects details of the labels, leaflets and or packaging (also known as livery) of the product, you will need to include the updated versions with your submission to be assessed.

However, you don’t need to submit a variation if there hasn’t been change to the product and you only want to make style changes to the labels, leaflets and/or packaging.

For example, if you’re changing the design of the leaflet and it has no relation to a change in the product, a variation application is not needed. See patient information leaflets for guidance on how to submit these types of changes.

Submit grouped changes (grouping)

You can apply multiple changes to a single product using the ‘grouping’ format, as long as the changes are directly related.

For example, you can make a change to the manufacturing site of the finished product, change in batch size and the manufacturing process to 1 product. The type of procedure (type IA, IB, II) depends on the extent of the change. You can see details of this in the annex of the EU guidelines.

You can submit grouped changes to an MA with multiple product licences under the European procedure.

If a type IA variation is included in a group with other types of variations, the type IA change should not be implemented until all changes for that group have been approved.

You can group any type IA and IAIN changes for different marketing authorisations, as long as the group only contains IA and IAIN changes and the changes are the same. All of these changes should be implemented before you notify MHRA.

Grouping applications for national MAs

For groupings where MAs were granted through a national procedure only, you will need to apply for grouped changes through that respective member state. For example, if 4 MAs (for 4 products) were granted in the UK, grouped changes such as a type IB with a type IA will need to be applied for through MHRA. If you have multiple products granted by Spain, for example, you would need to apply for grouped changes through their competent authority.

If you have multiple products and multiple MAs granted both nationally and at a European level, you may prefer to submit grouped changes using the worksharing process.

If your desired group of changes isn’t included in the guidance or the examples, you need to complete the grouping template
(MS Word Document, 26.5KB)
, copy and paste it into the main body of an email and send it to variationqueries@mhra.gov.uk before you submit your application. We aim to confirm if your grouping is acceptable within 7 working days.

Variations to multiple products (worksharing)

You can use the worksharing format if you’re submitting the same type IB or type II change or group of changes to multiple MAs.
Proposals for worksharing applications should be sent to:

the Coordination Group for Mutual Recognition and Decentralised Procedures (CMDh) if the MAs were granted under the mutual recognition and/or decentralised procedures and the reference member states were different
*the reference member state if the authorisations were granted under the mutual recognition and/or decentralised procedure and the reference member state is was the same for each MA

the competent authorities for the relevant countries if the MAs were granted under purely national procedures, email mr-dcprocedures@mhra.gov.uk for the UK.

Once MHRA have all the necessary documents, it will usually take 60 days to assess applications although it could take up to 120 days if the variation(s) are more complex or up to 30 days if urgent.

Composite coordination collection (CCC) - national pilot scheme

If you want to apply for changes to one or more product licences (licence for each product under a marketing authorisation) that would affect the product information you can submit a composite coordination collection (CCC). Product information includes the summary of product characteristics, leaflets and labels.

With a CCC you can:

submit only one consolidated mock-up of the leaflets and labels with all the changes proposed.

submit a mixture of variations applications and Article 61(3) applications

apply for single or grouped changes, such as a type IB and/or type II variations (see groupings)

Since January 2016 it has become mandatory for new marketing authorisation, renewal and variation application submissions to be made using electronic application forms (eAFs). This will apply to all procedure types, including national procedures. If you are making a submission using the portal, you will have to submit using the portal forms as well as submitting the eAF. If you are submitting your application through CESP you will only need to submit the eAF.

General CESP training is available to all registered users via CESP’s training menu once logged into the system. Training on demand videos are available and you can also sign up to our free online weekly live demonstrations. CESP encourage all users to attend training before using the system.
View FAQs here.

Supporting documents

Send a dispatch date list (detailing when you intend to dispatch the products) to all member states before submitting your application if your MA was granted through the mutual recognition or decentralised procedures. Where the UK is your reference member state, email this list to Type1aDDL@mhra.gov.uk for type IA changes and MR-DCprocedures@mhra.gov.uk for type IB and II changes and include a copy in the ‘additional data’ section of the eCTD format.

Type IA and IB

For type IA and IB variation applications you need to include:

a cover letter with your MA number, type of variation and reason for the variation

an explanation of your grouped variations if applicable, making specific reference to the Heads of Medicines Agencies (HMA) acceptable groupings guidance and examples of groupings
(PDF, 2.5MB, 12 pages)
or the confirmation email from MHRA agreeing you can submit grouped variations

present and proposed details of your product presented as a separate document if necessary

a contents page listing all documents included in your submission

Type II

For type II applications, you must include all of the above and:

relevant information to support your application such as publications and any cited references

a new or updated addendum to the ‘quality overall summary’, clinical and non-clinical overviews

Summary of product characteristics (SPC)

If relevant, the summary of product characteristic fragments (SPC) should be submitted to MHRA in the correct format using the templates below. If you do not use these templates your submission will be rejected.

These templates should not be altered in any way, other than inserting the relevant information. They should be saved using the following naming conventions in the ‘workingdocuments’ folder of your eCTD:

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